Access to thioethers from thiols and alcohols via homogeneous and heterogeneous catalysis

A metal-free dehydrative thioetherification method has been reported, enabling the conversion of various alcohols and thiols into thioethers. By employing triflic acid as a catalyst or utilizing a recyclable NAFION® superacid catalyst, these methods significantly improve the efficiency and practicality of sulfide preparation.

available thiols and alcohols were purchased from Sigma Aldrich (Merck), Angene or Ambeed, and used as received.The progress of reactions (conversion of thiols) was monitored by GC chromatography using Bruker Scion 460-GC and Agilent 5977B GC/MSD with Agilent 8860 GC System.The structures of products were determined by NMR spectroscopy, IR spectroscopy, and MS spectrometry.The 1 H NMR (400 or 600 MHz), and 13 C NMR (101 or 151 MHz) spectra were recorded on Bruker Avance III HD NanoBay spectrometer, using chloroform-d (CDCl 3 ) as the solvent.Deuterated solvents were purchased from Sigma Aldrich (Merck) (CDCl 3 99.8 atom% D) and used as received.The enantiomeric purity was determined by HPLC analysis (Daicel Chiralcel OD-H).FT-IR spectra were taken on a Nicolet™ iS50 FTIR Spectrometer.In the case of IR spectroscopy in real-time, the measurements were made using a ReactIR 15 Mettler Tolledo spectrophotometer, equipped with a 9-reflection probe with a diamond window of 9.5 mm AgX DiComp Mettler Tolledo and an MCT detector cooled with nitrogen.

General synthetic procedures
All procedures can be also found in Supporting Information.Here, we present representative procedures.

The synthesis of compounds 3a-3p and 3aa-3af
To a 10 mL vial equipped with a magnetic stirring bar, alcohol (1, 1 mmol), thiol (2, 1 mmol), nitromethane (1 mL), and HOTf (0.01 mmol) were added under an ambient atmosphere.Subsequently, the reaction mixture was stirred at 80 °C for 2 h.After the reaction was completed, in order to neutralize HOTf the potassium carbonate (0.01 mmol) was added.After this time, the solvent was evaporated under reduced pressure.Next, the crude products were separated via extraction (diethyl ether-water), to give corresponding products 3a-3p, and 3aa-3af.The pure products were identified by 1 H NMR, 13 C NMR, IR, and MS spectrometry.

The synthesis of compounds 3q and 3r
To a 10 mL vial equipped with a magnetic stirring bar, alcohol (1, 2 mmol), thiol (2, 1 mmol), nitromethane (1 mL), and HOTf (0.02 mmol) were added under an ambient atmosphere.Subsequently, the reaction mixture was stirred at 80 °C for 2 h.After the reaction was completed, in order to neutralize HOTf the potassium carbonate (0.02 mmol) was added.After this time, the solvent was evaporated under reduced pressure.Next, the crude products were separated via extraction (diethyl ether-water), to give corresponding products 3q-3r.The pure products were identified by 1 H NMR, 13 C NMR, IR, and MS spectrometry.www.nature.com/scientificreports/The synthesis of compounds 3ag-3am, and 3ao-3ap To a 10 mL vial equipped with a magnetic stirring bar, alcohol (1, 1 mmol), thiol (2, 1 mmol), nitromethane (1 mL), and HOTf (0.05 mmol) were added under an ambient atmosphere.Subsequently, the reaction mixture was stirred at 80 °C for a definite time (2-6 h).After the reaction was completed, in order to neutralize HOTf the potassium carbonate (0.01 mmol) was added.After this time, the solvent was evaporated under reduced pressure.Next, the crude products were separated via extraction (diethyl ether-water), to give corresponding products 3ag-3am, and 3ao-3ap.The pure products were identified by 1 H NMR, 13 C NMR, IR, and MS spectrometry.

Results and discussion
The optimization studies, presented in Table 1, involved an in-depth investigation of a dehydrative coupling reaction between thiophenol (2a) and tert-amyl alcohol (1a).Significantly, all experiments were carried out utilizing new vials and magnetic stirrers.This meticulous approach holds immense significance in eradicating any potential impact stemming from trace amounts of other transition metal impurities 50,51 .Since the substrates are not air-sensitive, we performed all reactions under an ambient atmosphere.Importantly, comprehensive details related to optimization studies (especially the use of metal triflates as the catalysts) can be found in the Supporting Information file (Table S1).
Initially, we tested the activity and selectivity of simple HOTf in a dehydrative coupling reaction (Table 1).The optimal attempt was conducted in CH 3 NO 2 as a solvent (80 °C, 2 h), in the presence of 1 mol% of HOTf.As a result, we obtained the desired product 3a in 90% yield (entry 1).Attempt to decrease the loading of the catalyst gave a bit inferior conversion (entry 2).The control reaction revealed that the process does not proceed without the catalyst (entry 3).Instead, it was found that the reaction works under solvent-free conditions.However, in such a case we observed the formation of three different thioethers (entry 4).Finally, several solvents including H 2 O, 2-MeTHF, and CH 3 CN were utilized (entries 9-11).We demonstrated that nitromethane was the solvent of choice (other mediums were less efficient and provided noticeably lower chemoselectivity).The above-mentioned processes can also proceed in the presence of commercially available metal triflates (for details please see Table 1, entry 7 and 8, as well as SI, Table S1).
Having the optimized conditions at our disposal, we conducted tests using various thiols to demonstrate the broad applicability of our protocol (Fig. 2, top).The reaction conditions proved to be effective for a diverse set of thiophenol derivatives (3a-3j).As an initial example 3a, benzenethiols bearing electron-donating groups were readily alkylated (3b-3e), including difunctional 4-hydroxythiophenol 3d (88% yield).Gratifyingly, halogenated thiophenols were readily adopted in this protocol (3f-3h, 82-84% yield), as were electron-deficient ones bearing trifluoromethyl and trifluoromethoxy functionalities (3i-3j, 87% yield).Motivated by these findings, we subsequently explored the utilization of heterocyclic thiols, which serve as biorelevant frameworks.Each of them yielded the desired products with moderate efficiencies (3k-3l, 70-73% yields).Next, we were pleased to find that HS-terminated carboxylic acids and esters were also successfully alkylated under standard conditions leading to products 3m-3n in very good yields (85-90%).
Lastly, the reaction on a larger scale demonstrated the robustness and preparative scale utility of the process, under procedurally convenient conditions (Fig. 3).
The concept of Brønsted acid catalysis mentioned above motivated us to explore a heterogeneous system using Nafion®, a perfluorinated copolymer with sulfonic acid groups.This particular copolymer has proven useful in dehydration and esterification reactions [52][53][54] .In our experiment, we initially selected benzenethiol (1 mmol) and tert-amyl alcohol (1.5 mmol) as the coupling partners.We conducted the reaction using approximately 0.22 g of Nafion® NR50 pellets (approx.5 pellets) (Fig. 4, top).To obtain a detailed understanding of the heterogeneous catalyst, we became intrigued to further probe its reusable nature (Fig. 4, bottom).We were hence delighted to observe that Nafion was successfully reused without a significant loss of performance over 10 cycles.
Next, to get some mechanistic insights into Brønsted acid catalysis, we carried out some of preliminary experiments (Fig. 5).As a first investigation, we conducted a radical clock experiment.It gives the desired product containing an untouched cyclopropyl ring (3z), thereby implying that radical pathways were likely, not operative  www.nature.com/scientificreports/(Fig. 5a).Therefore, the most probable mechanism involves the S N 1-type nucleophilic substitution.With the formation of a planar sp 2 hybridized carbocation, racemization occurs.Confirmation of this reaction pathway is provided by using an R-enantiomer of 1-phenylethan-1-ol.As a result, a racemic mixture was observed (Fig. 5b).Next, we monitored the dehydration reaction using reactIR (Fig. 5c).The kinetic plots obtained for the coupling of tert-amyl alcohol (1a) to thiophenol (2a) confirmed a rapid disappearance of the distinguishing bands at 880 and 940 cm −1 (Fig. 5c).Thus, a mechanism is presented in Fig. 5d.Finally, we proceeded to find an answer to the question of whether this reaction can occur using both Brønsted and Lewis catalysis.In this case, the hydrolysis of metal triflates is known to occur with the formation of triflic acid.Therefore, we conducted a test reaction using indium(III) triflate as the catalyst.However, we carried it out in the presence of 2,6-di-tert-butylpyridine, which does not coordinate to Lewis acids but readily undergoes protonation.Despite the use of pyridine, the reaction proceeded unchanged in terms of efficiency and selectivity, suggesting that both Brønsted and Lewis acids can catalyze this reaction (Fig. 5e).

Conclusions
In summary, we have successfully developed an innovative metal-free approach for thioesterification of alcohols utilizing thiols.Unlike previous methods that heavily relied on transition metals or metal triflates, our new method offers distinct advantages.Through our studies, we have demonstrated that a simple triflic acid serves as a highly efficient and selective catalyst.Moreover, we have addressed practicality concerns by exploring the option of heterogeneous catalysis using superacidic Nafion.This exciting development allows for the catalyst's repeated usage without significant loss in process efficiency.Furthermore, our research has provided valuable insights into the reaction mechanism.In addition, we conducted a comparison between Lewis acid and Brønsted acid catalysis, revealing that both approaches exhibit equally remarkable effectiveness.These significant advancements open up exciting possibilities for sustainable and green thioesterification processes, with reduced environmental impact and enhanced applicability in industrial and pharmaceutical contexts.

Figure 1 .
Figure 1.Context of the investigation.

Figure 4 .
Figure 4. Dehydrative thioetherification of alcohols in the presence of Nafion catalyst.